Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

Abstract

Coenzyme Q₁₀ (CoQ₁₀) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ₁₀ supply (redox homeostasis, ferroptosis and sulfide oxidation). The CoQ₁₀ biosynthesis pathway consists of several enzymes, which are encoded by the nuclear DNA. The majority of these enzymes are responsible for modifications of the CoQ-head group (benzoquinone ring). Only three enzymes (PDSS1, PDSS2 and COQ2) are required for assembly and attachment of the polyisoprenoid side chain. The head-modifying enzymes may assemble into resolvable domains, representing COQ complexes. During the last two decades, numerous inborn errors in CoQ₁₀ biosynthesis enzymes have been identified. Thus far, 11 disease genes are known (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9 and HPDL). Disease onset is highly variable and ranges from the neonatal period to late adulthood. CoQ₁₀ deficiency exerts detrimental effects on the nervous system. Potential consequences are neuronal death, neuroinflammation and cerebral gliosis. Clinical features include encephalopathy, regression, movement disorders, epilepsy and intellectual disability. Brain magnetic resonance imaging (MRI) is the most important tool for diagnostic evaluation of neurological damage in individuals with CoQ₁₀ deficiency. However, due to the rarity of the different gene defects, information on disease manifestations within the central nervous system is scarce. This review aims to provide an overview of brain MRI patterns observed in primary CoQ₁₀ biosynthesis disorders and to highlight disease-specific findings.

Keywords: Leigh syndrome; mitochondrial oxidative phosphorylation; multiple system atrophy; neurodegeneration; ubiquinone.

Figure 1

The multiple functions of CoQ₁₀ in cell metabolism. CoQ₁₀ is important for the function of numerous cellular pathways (upper panel). However, it is best known for its role in as an electron carrier within the mitochondrial respiratory chain (lower panel). In addition, it functions as a reactive oxygen species (ROS) scavenger that protects the cell against oxidative stress. Created with BioRender.com (accessed on 31 January 2023).

Figure 2

Neuroimaging in PDSS1 deficiency: Brain MRI (T2-weighted, axial view) of a 24-month-old boy with PSSD1 deficiency. Extensive leukoencephalopathy is visible with cystic white matter lesions in the occipital regions. Other MRI images of this individual were published previously [16].

Figure 3

Neuroimaging in COQ4 deficiency: (A) Brain MRI, T2-weighted, coronal images of a 15-month-old girl with COQ4 deficiency. Images show bilateral circumscribed lesions in the subthalamic nuclei (white arrows). (B) Sagittal T1-weithed MRI images show no cerebellar lesions. (C) Brain MRI, T1-weighted, axial images of an 18-month-old girl with COQ4 deficiency showing global brain atrophy. (D) Brain MRI, T1-weighted, axial images of the same child showing cerebellar degeneration with bilateral large cysts within the cerebellar hemispheres (white arrows). (E,F) T2-weighted, coronal and sagittal images and of a 2-month-old girl with COQ4 deficiency showing cerebellar hypoplasia (white arrow). Other MRI images of these individuals were published previously [30].

Figure 4

Neuroimaging in COQ7 deficiency: (A) Brain MRI, T2-weighted, axial images of a 10-month-old boy with COQ7 deficiency. The MRI shows global brain atrophy and areas of encephalomalacia in bilateral frontal lobes. In addition, symmetric cystic changes within the putamen are visible (white arrows). (B) No cerebellar abnormalities are visible. Other MRI images of this individual were published previously [41].

Figure 5

Neuroimaging in COQ8A deficiency: Brain MRI (T1-weighted images, (A) axial view; (B) coronal view; (C) sagittal view) of a 60-year-old female with COQ8A deficiency. Images show cerebellar atrophy. Other MRI images of this individual were published previously [45].

Figure 6

Neuroimaging in HPDL deficiency: (A) Brain MRI, T2-weighted images of a 3-month-old girl with HPDL deficiency. Images show subcortical T2-hyperintensities, mainly affecting the right frontotemporal regions. Moreover, asymmetrical signal abnormalities of the thalami are visible (white arrows). (B) No cerebellar abnormalities are visible.